The biological activities of thyroid hormone (T3) are mediated by the thyroid hormone receptors (TRs). There are two TR genes, a and b, which yield TRa1, TRb1, TRb2 and TRb3 by alternative splicing of the primary transcripts. In the past years, we have been using the powerful mouse genetics not only to understand the molecular mechanisms of thyroid hormoe action in vivo, but also to delineate the molecular basis of diseases due to mutations of receptors. Creating a mouse model of thyroid hormone resistance syndrome (RTH) RTH is a disease due to mutations of the TRb gene. A mutation derived from an RTH patient at NIH (TRbPV) was targeted to the TRb gene locus via homologous recombination (TRbPV mouse). TRbPV mice faithfully reproduce human RTH. Using this mouse mode, it has become possible to study several critical, clinically relevant issues that previously could not be studied. We showed that RTH symptoms are caused by the dominant negative action of mutant TRb in vivo. We also discovered that variable phenotypic expression in RTH patients is dictated by tissue-dependent abundance of TRb and TRa1 isoforms. Identifying TRbPV mouse as a model of thyroid carcinogenesis An unexpected but remarkable discovery is that TRbPV/PV mice spontaneously develop thyroid carcinoma with sequential capsular invasion, vascular invasion, anaplasia, and eventually metastasis. The lack of valid mouse models with metastatic spread has impeded understanding of the molecular events of thyroid cancer invasion and metastasis. Thus, this mouse model contributes an unprecedented opportunity for investigators to study the alterations in gene regulation that occur with clinically relevant changes during progression and metastasis in a predictable fashion. Identification of signature genes at each step of thyroid carcinogenesis in these TRbPV/PV mice will certainly benefit diagnosis and treatment of thyroid cancer patients. Creating a novel mouse model (TRaPV mice) to elucidate the genetic basis of human dwarfism The intriguing observation that no mutations of the TRa gene have ever been identified in RTH patients has perplexed investigators for years and raised the fundamental issue of whether mutations of the TRa gene are lethal or can cause other human diseases. We have successful created the first TRa knockin mutant mouse unequivocally resolved this fundamental issue. The mutation of one allele of the TRa gene is not lethal, but results in dwarfism and other abnormalities that are clearly distinct from RTH. The demonstration that the mutation of the TRa gene leads to dwarfism has generated significant excitement in the field. This mouse model is being used to study possible TRa mutations in children with growth abnormalities. Identifying TRa1 isoform as the mediator of brain functions Thyroid hormone is essential for normal development of the nervous system. Cretinism results from the lack of thyroid hormone during the critical development period. Using the two mice harboring either the TRaPV or TRbPV mutant gene described above, we have discovered that it is the TRa1, not TRb isoform that mediates the in vivo local cerebral glucose utilization that is linked to neuronal functional activity. The TRa1-mediated reduction in glucose utilization is due to the decrease in synaptic formation. Discovering the critical role of TR co-activators in the pathogenesis of RTH and thyroid carcinogenesis The transcriptional activity of TRs is activated by co-activators such as the steroid hormone receptor co-activator-1 (SRC-1). To study the role of co-activator in RTH and thyroid carcinogenesis, we crossed the TRbPV mice with SRC-1 knockout mice and found that the lack of SRC-1 intensifies the resistance of tissues in RTH. These results demonstrate the important in vivo role of TR co-activators in the pathogenesis of RTH. Importantly, for the first time, we discovered that the progression of thyroid carcinogenesis is accelerated by the lack of SRC-1, suggesting that SRC-1 could potentially act as a tumor suppressor in thyroid carcinogenesis. The possible role of SRC-1 as a tumor suppressor is currently being investigated. These novel findings have important clinical implications.